SUMMARY Controlling specific neural circuits across large areas of the brain is a major technology goal of the BRAIN Initiative. To achieve this goal, technologies should ideally provide a combination of spatial, temporal and cell- type specificity and be noninvasive to facilitate their translation across animal models and, ultimately, human patients. Here, we propose an approach to modulating neural circuits noninvasively with spatial, cell-type and temporal specificity. This approach, which we have named Acoustically Targeted Chemogenetics, or ATAC, uses transient focused ultrasound (FUS) blood brain barrier opening (BBBO) to transduce neurons at specific locations in the brain with virally-encoded engineered receptors, which subsequently respond to systemically administered bio-inert compounds to activate or inhibit the activity of these neurons. This technology allows a brief, noninvasive procedure to make one or more specific brain regions capable of being selectively modulated using orally bioavailable compounds. In preliminary experiments, we have implemented this concept in mice by using ATAC to noninvasively target AAV9 viral vectors encoding chemogenetic DREADD receptors to excitatory neurons in the hippocampus, and showing that this enables pharmacological inhibition of memory formation. Building on this proof of concept, we will now scale ATAC to work in non-human primates. This goal is particularly important given the relatively limited success of existing technologies, including optogenetics and conventional chemogenetics, in robust behavioral neuromodulation in larger animals. Scaling ATAC to larger animals requires several innovations beyond the core concept, including evolving viral vectors for more efficient and intersectional transfection of neurons with FUS-BBBO, developing ultrasound methods to overcome skull aberrations and enable precise targeting in large animals, establishing ways of confirming the functionality of ATAC non- invasively with functional imaging, and optimizing the selection and pharmacological administration of chemogenetic ligands for large-animal behavioral studies. In this project, we will first establish the basic capabilities of ATAC in NHPs and integrate them with non-invasive functional imaging, setting a baseline for ATAC performance. Then, we will use a pioneering technology for in vivo evolution of viral vectors to develop AAV viruses specifically optimized to efficiently deliver chemogenetic receptors to brain regions targeted with FUS-BBBO. In parallel, we will develop non-clinical image guidance and aberration correction methods to enable precise targeting and verification of FUS-BBBO in NHPs. This will make it possible for academic groups without access to expensive clinical FUS systems to perform ATAC in larger organisms. Finally, as motivating example applications, we will demonstrate that the optimized ATAC paradigm can be used to inhibit multiple distinct brain regions in macaques, reversibly and repeatably modulating their ability to recognize faces and also apply it in a sensorimotor circuit to alter functional connectivity. We will also show its stability, reliability and non-toxicity.